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Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models
- Source :
- Cell Death and Disease, Vol 11, Iss 2, Pp 1-18 (2020), Cell Death & Disease
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
Abstract
- Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson’s disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.
- Subjects :
- Cell death
Cancer Research
Programmed cell death
Curcumin
Parkinson's disease
Immunology
ATG5
Oxidative phosphorylation
Ascorbic Acid
medicine.disease_cause
Neuroprotection
Article
Antiparkinson Agents
Cellular and Molecular Neuroscience
Parkinsonian Disorders
Cell Line, Tumor
Macroautophagy
medicine
Autophagy
Animals
Humans
Naphthyridines
lcsh:QH573-671
Oxidopamine
Behavior, Animal
Chemistry
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
lcsh:Cytology
Dopaminergic Neurons
TOR Serine-Threonine Kinases
Mitophagy
Brain
Cell Biology
Ascorbic acid
Cell biology
Mice, Inbred C57BL
Disease Models, Animal
Oxidative Stress
nervous system
TFEB
Female
Oxidative stress
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 11
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cell Death and Disease
- Accession number :
- edsair.doi.dedup.....b789f1201845cefe6f8cfe24260813c2